title: A competitive protein interaction network buffers Oct4-mediated differentiation to promote pluripotency in embryonic stem cells.
abstract: Pluripotency in embryonic stem cells is maintained through the activity of a small set of transcription factors centred around Oct4 and Nanog, which control the expression of 'self-renewal' and 'differentiation' genes. Here, we combine single-cell quantitative immunofluorescence microscopy and gene expression analysis, together with theoretical modelling, to investigate how the activity of those factors is regulated. We uncover a key role for post-translational regulation in the maintenance of pluripotency, which complements the well-established transcriptional regulatory layer. Specifically, we find that the activity of a network of protein complexes involving Nanog, Oct4, Tcf3, and β-catenin suffices to account for the behavior of ES cells under different conditions. Our results suggest that the function of the network is to buffer the transcriptional activity of Oct4, which appears to be the main determinant to exit pluripotency. The protein network explains the mechanisms underlying the gain and loss of function in different mutants, and brings us closer to a full understanding of the molecular basis of pluripotency.
authors.affiliation: 1] Department of Genetics, University of Cambridge, Cambridge, UK [2] Biology and Biochemistry Department, University of Bath, Bath, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: Muñoz Descalzo
authors.forename: Pau
authors.initials: P
authors.lastname: Rué
authors.forename: Fernando
authors.initials: F
authors.lastname: Faunes
authors.forename: Penelope
authors.initials: P
authors.lastname: Hayward
authors.forename: Lars Martin
authors.initials: LM
authors.lastname: Jakt
authors.forename: Tina
authors.initials: T
authors.lastname: Balayo
authors.forename: Jordi
authors.initials: J
authors.lastname: Garcia-Ojalvo
authors.forename: Alfonso
authors.initials: A
authors.lastname: Martinez Arias
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D004622:Embryo, Mammalian; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3 / Q000235:genetics* / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D060066:Protein Interaction Maps / Q000235:genetics*; D015398:Signal Transduction; D059010:Single-Cell Analysis; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; D051176:beta Catenin; C495267:CTNNB1 protein, mouse; C475540:Nanog protein, mouse; C494174:Pou5f1 protein, mouse; C075668:Tcf3 protein, mouse